tbuckley/cabot-search huggingface dataset:
A phase 2 basket study of tucatinib and trastuzumab in previously treated solid tumors with HER2 alterations: Urothelial cancer cohort (SGNTUC-019).
Authors: Evan Y. Yu, Fan Jin, Jorge Ramos, Qianwen Tan, Matt D. Galsky
Journal: Journal of Clinical Oncology (2023)

TPS587 Background: Tucatinib, a highly selective human epidermal growth factor receptor 2 (HER2)-directed tyrosine kinase inhibitor approved in multiple regions for HER2-positive (HER2+) metastatic breast cancer, is being investigated as a novel therapy for metastatic colorectal cancer, gastric cancer, and other solid tumors. In xenograft models of HER2+ and HER2-mutated tumors, dual targeting of HER2 with tucatinib plus trastuzumab showed superior activity to either alone (Kulukian 2020; Peterson 2020). Despite development of several new therapies for metastatic urothelial cancer (UC), most patients are refractory to subsequent therapies and die from the disease, highlighting the need for additional therapeutic approaches. Given that 20%–30% of metastatic UCs have molecular alterations of the ErbB family, tucatinib plus trastuzumab warrants further evaluation. SGNTUC-019 (NCT04579380) is a multi-cohort, open-label, phase 2 study evaluating tucatinib plus trastuzumab in patients with previously treated solid tumors displaying HER2+ or HER2-mutated solid tumors, including a cohort with locally advanced or metastatic UC. Methods: Eligible patients in the UC cohort must have HER2+ locally advanced or metastatic disease, with progression during or after, or intolerance of, the most recent line of systemic therapy. Patients must have an ECOG PS ≤1; adequate hepatic, hematologic, renal, and cardiac function; and no prior exposure to HER2-directed therapy. HER2 alterations can be demonstrated by HER2 overexpression/amplification in tumor tissue by prior IHC/ISH or by HER2 amplification in prior or prescreening NGS assay of ctDNA or prior tissue NGS assay. The HER2 overexpression/amplification UC cohort will enroll 12 response-evaluable patients per RECIST 1.1. If ≥2 responses are observed, the cohort will be expanded to 30. The primary objective is antitumor activity, with confirmed ORR as the primary endpoint and DCR, duration of response, PFS, and OS as secondary efficacy endpoints. Confidence intervals (CIs) will be calculated for confirmed ORR and DCR. For time-to-event endpoints, median survival time will be estimated by the Kaplan-Meier method, and the associated 95% CI will be calculated using complementary log-log transformation. Safety endpoints will be assessed using descriptive statistics. Patients will receive tucatinib 300 mg orally twice daily and trastuzumab 8 mg/kg intravenously on Cycle 1 Day 1 and 6 mg/kg every 21 days from Cycle 2 Day 1. Disease assessments per RECIST 1.1 will occur every 6 weeks for 24 weeks, then every 12 weeks. Trough concentrations of tucatinib will be evaluated in Cycles 2–6, with peak concentration sampled in Cycle 3. Quality of life will be evaluated every second cycle using the EQ-5D-5L. Sites are currently enrolling within the US, EU, and Asia Pacific. Clinical trial information: NCT04579380 .
Complimentary genomic, pathologic, and artificial intelligence analysis on low-grade noninvasive bladder cancer to predict downstream recurrence.
Authors: Kyle M. Rose, Aram Vosoughi, Gustavo Borjas, Heather L Huelster, Philippe E. Spiess, Anders E. Berglund, Wade J. Sexton, Anirudh Joshi, Nagi B. Kumar, Roger Li
Journal: Journal of Clinical Oncology (2023)

553 Background: Low-grade noninvasive (LGTa) bladder cancer is a relatively quiescent but heterogenous malignancy, characterized by downstream recurrences requiring repeated transurethral resections and frequent surveillance. Investigations to elucidate drivers of recurrence have been sparse, but will help risk-stratify patients with LGTa and allow augmentation of follow up protocols. Methods: Patients with LGTa index tumors were stratified by those with no downstream recurrences (nonrecurrent) vs. those with later recurrences (recurrent). RNA sequencing identified differentially expressed genes (DEGs), deconvoluted for cell-type using xCell. Pathologic analysis was performed by a genitourinary pathologist, then a deep-learning artificial intelligence (AI) platform was leveraged to correlate recurrence risk and recurrence-free survival (RFS) based on deep-learning algorithm of segmented nuclei. Results: Thirty index bladder tumors/patients were identified, 18 (60%) of which had later recurrence (Table). There were 238 DEGs recognized, with recurrent tumors expressing signatures for epithelial mesenchymal transition, myogenesis, TNFα signaling via NFκB, and angiogenesis. Recurrent tumors also demonstrated a higher tissue micoenvironment, stroma, and cancer-associated fibroblast score. Pathologic TME analysis validated these findings, with recurrent tumors demonstrating a higher frequency of inverted growth pattern and a higher median stroma percentage. Finally, the AI-derived signature was predictive of recurrence and risk-stratified the cohort (HR= 5.43 [95% CI 1.1-26.76]) for predicting high vs. low risk of recurrence. Patients in the high risk group had a 87.5% recurrence rate while those in the low risk group had a 28.5% recurrence rate (p&lt;0.01). Conclusions: Using a multi-disciplinary approach, we identified key signatures in recurrent LGTa bladder cancer. Characterization of these factors is a critical first step in the risk-stratification of LGTa tumors, and may allow risk-stratification of surveillance protocols and identification of possible targets for chemoprevention trials. [Table: see text]
RIPK2 as a prognostic biomarker and predictor of aggressive prostate cancer.
Authors: Mustafa Hammudi, Walaa Aldhahri, Akshar Kalola, Catherine McCullum, Caddie Motoni, Antonio Martha, Rithika Rajendran, Victor Nava, Fayez Estephan, Morgan Byrne, Guoqing Diao, Maneesh Rajiv Jain
Journal: Journal of Clinical Oncology (2023)

211 Background: Receptor-Interacting Protein Kinase 2 (RIPK2) has been known to play a significant role in inflammation and anti-microbial response via the NF-KB pathway. Recently, RIPK2 was also shown to stabilize and activate c-Myc, a molecule implicated in the progression of various malignancies including prostate cancer (PCa). Our study aims to determine the prognostic value of RIPK2 expression in PCa using immunohistochemistry (IHC) analysis of biopsy specimens with special focus on a predominantly African American (AA) cohort. Methods: Eligible patients aged ≥18 years diagnosed with PCa at the Washington DC VA Medical Center were randomly selected and retrospectively grouped into indolent, locally advanced, and metastatic disease categories and stratified by age, ethnicity, AJCC stage, PSA and Gleason score at diagnosis. Representative tissue from prostate core biopsy, transurethral resection, or radical prostatectomy was analyzed for each patient. RIPK2 expression and intensity were assessed by IHC and graded by two independent pathologists by the following scale: 0 (no cytoplasmic staining), 1+ (weak cytoplasmic staining similar to benign prostatic tissue), 2+ (moderate cytoplasmic staining), and 3+ (strong cytoplasmic staining). The primary endpoint was RIPK2 expression by disease group, and key secondary outcomes were RIPK2 association with Gleason score, PSA at diagnosis, age and race. Fisher’s exact test was used to evaluate statistical significance of the association between RIPK2 expression level and disease category. Results: A total of 89 patients were selected for analysis, of which 75 (84.3%) were AA. All tumors had at least 1+ level RIPK2 expression and there was a highly significant difference in RIPK2 expression according to disease severity (p &lt; 0.001). Stratified RIPK2 expression was 1.53, 1.83, and 2.28 in the indolent, locally advanced, and metastatic groups respectively. We observed a significant directly proportional correlation between RIPK2 expression and a higher PSA level (p= 0.0021), Gleason score (p&lt; 0.001), higher age (p= 0.0276), and AJCC stage (p&lt; 0.001) at the time of diagnosis. Mean RIPK2 expression was 1.81 in AA patients and 2.15 in White patients (p= 0.0332). Conclusions: PCa is the most prevalent cancer in US males and there is an urgent need for more accurate biomarkers that can predict disease severity and suggest actionable targeted therapy. In this retrospective analysis, we confirm that higher RIPK2 expression is associated with more advanced PCa. We extend these findings to a predominantly AA cohort, which may promote improvements in personalized medicine for this population at higher risk for PCa if RIPK2-targeting drugs such as Ponatinib can be utilized.
Incidence and survival in patients with urachal carcinoma: Cancer registry analysis between 2008 and 2019.
Authors: Christopher Darr, Lennart Möller, Niklas Schürger, Tibor Szarvas, Henning Reis, Andreas Stang, Boris A. Hadaschik, Hiltraud Kajüter, Viktor Grünwald
Journal: Journal of Clinical Oncology (2023)

480 Background: Urachal carcinoma (UrC) is a rare and poorly studied cancer without evidence-based treatment strategies. Due to the low prevalence of this cancer, only sparse data on its incidence and survival are available. Therefore, we analyzed the incidence and survival rates of patients with UrC in North Rhine-Westphalia (NRW), a state of the Federal Republic of Germany. Methods: UrC (ICD-O-3: C67.7) diagnosed between 2008 and 2019 were identified via the NRW Cancer Registry (population 18 million) and classified according to Mayo-staging and T-category. Mayo stage was based on the TNM classification. We calculated age-standardized incidence rates using the European standard and Kaplan-Meier overall survival (OS). Age was stated as mean and standard deviation (SD). Results: A total of 121 UrC patients were described, of which men were more frequently affected at 57%. The distribution for women was 43%. The mean age was 61.1 (SD: 15.5) years for men and 58.8 (SD: 15.3) years for women. The overall age-standardized incidence rate was 0.43 per 1.000.000 person-years, which was 0.5 for men and 0.37 for women. 85.1% had adenocarcinomas, 6.6% urothelial carcinoma, 4.1% unspecified cancer, 2.5% epithelial carcinomas, 0.8% squamous cell carcinomas or others, respectively. The 5-year OS rate were 60.4% (CI-95%: 48.9%; 74.7%) for men and 41.7% (CI-95%: 28.8%; 60.2%) for women. According to TNM classification, 33% of the patients presented with T1-2, 29.8% with T3-4, while for the Mayo staging a distribution of 17.4% for stage I-II and 13.2% for stage III-IV was shown. Data regarding T-category and Mayo-satging were available in 63.6% (44 patients) and 30.6% (84 patients), respectively. The 5-year OS was 73.3% (CI-95%: 59.3%; 90.6%) in T1-2, 37.2% (CI-95%: 23.6%; 58.6%) in T3-4. and 69.3% (CI-95%: 47.6%; 100%) and 25.6% (CI-95%: 9.89%; 66.49%) in Mayo stage I-II and III-IV, respectively. Conclusions: UrC is a rare cancer and OS rate in NRW were comparable to historical data. The prognosis was stage-dependent and identified poor outcome in patients with advanced disease. Our data underscored the role of proper staging and diagnosis for future clinical studies that investigate optimal treatment strategies.
Adjuvant immunotherapy for patients with renal cell carcinoma at increased risk of recurrence following resection: A National Cancer Database analysis.
Authors: Harshit Garg, Mukund Bhandari, Onika Noel, Furkan Dursun, Michael A. Liss, Dharam Kaushik, Deepak K Pruthi, Robert S. Svatek, Chethan Ramamurthy, Ahmed M Mansour
Journal: Journal of Clinical Oncology (2023)

649 Background: Radical nephrectomy is the standard management for locoregional renal cell carcinoma (RCC); however, patients with adverse pathological features are at increased risk of recurrence. IMmotion010 and KeyNote 564 trials investigated the adjuvant role of immune checkpoint inhibitors (ICI) for high-risk clear cell RCC (ccRCC) and have yielded conflicting results. We aimed to investigate real-world survival outcomes associated with the adjuvant use of ICI in high-risk ccRCC using the National Cancer Database Methods: In this nationwide contemporary cohort study, patients with newly diagnosed non-metastatic high-risk clear cell RCC undergoing radical nephrectomy between 2015-2019 were included. High-risk RCC was defined as cT2 with Fuhrman grade 4 or cT3a with Fuhrman grade 3/4 or cT3b/T3c/T4 with any grade, or TxN+ any grade. Patients receiving adjuvant ICI were classified as Group A and patients who did not receive adjuvant ICI were classified as Group B. Inverse probability weighting (IPW)-adjusted Kaplan Meier curves were utilized to compare overall survival (OS) between the groups and cox proportional hazard models were utilized to identify the predictors for OS. Results: Overall, 768 patients met the inclusion criteria; 270 patients in Group A and 498 patients in Group B. The mean age was 60.5(10.6) years, and 70.8% of patients were males (Table). The use of ICI in the adjuvant setting for high-risk RCC increased from 17.4% in 2015 to 61.8% in 2019. The unadjusted and IPW-adjusted Kaplan Meier 5-year overall survival was similar in the two groups [Unadjusted: 36.8% in Group A vs 50.1% in Group B, p=0.30 and adjusted: 39.5% in Group A vs 47.9% in Group B, p=0.17]. The use of adjuvant ICI did not appear to be an independent predictor for OS on multivariable cox regression analysis (HR=1.14, p=0.31) Conclusions: Adjuvant ICI therapy in non-metastatic high-risk ccRCC might not be associated with a benefit in overall survival. [Table: see text]
Assessing the utility of a cell-free tumor (ct)DNA assay (MSK-ACCESS) in patients (pts) with node-positive (N+) muscle-invasive bladder cancer (MIBC) undergoing neoadjuvant chemotherapy (NAC).
Authors: Andrew B Katims, Andrew T Lenis, Ronak H. Shah, Carissa E Chu, Neha Ratna, Ashley M Regazzi, Eugene J. Pietzak, David H Aggen, Samuel A Funt, Min Yuen Teo, Jonathan E. Rosenberg, Dean F. Bajorin, Timothy F. Donahue, Bernard H. Bochner, Michael F. Berger, David B. Solit, Gopa Iyer
Journal: Journal of Clinical Oncology (2023)

544 Background: Circulating ctDNA is associated with disease progression, worse overall survival, and recurrence in pts with bladder cancer. This study correlated targeted exome ctDNA sequencing with pathologic response to NAC and metastatic recurrence in pts with N+ MIBC undergoing radical cystectomy (RC). Methods: We prospectively identified pts with cT2-3N1-2M0 bladder cancer who underwent NAC prior to RC. Node positivity was determined radiographically and/or by node biopsy. Plasma samples were collected pre-NAC, mid-treatment, after NAC completion, and 3 months after RC. Samples were analyzed using MSK-ACCESS, an ultrasensitive ctDNA platform designed to identify somatic mutations in 129 cancer associated genes. Primary bladder tumors were sequenced using targeted exome sequencing. Results: Samples (31) from 9 pts (6 men) were analyzed. Median age was 63 years (IQR 58-69). NAC regimens included gemcitabine and cisplatin alone (78%) or with paclitaxel (22%). Seven (78%) pts had &gt;1 detectable mutation pre-NAC. The most altered genes detected in both tissue and ctDNA included: TERT (88% vs 28%), TP53 (76% vs 40%), ARID1A (43% vs 17%), RB1 (43% vs 15%), KDM6A (43% vs 15%), and ATM (17% vs 17%). Four (45%) pts had complete response (ypT0N0), 1 (11%) had a partial response (ypT1N0), and 4 (33.3%) were non-responders (ypT2N0-3). All non-responders had disease recurrence after RC (median 3 months, range 2-11 months). Of 7 pts with on-treatment MSK-ACCESS, 2 (29%) had detectable ctDNA (1 ypT2N0, 1 ypT0N0). The pt with a PR had detectable ctDNA post-NAC with 1 mutation identified that was not detected at 3 months. All pts with &gt;ypT2N0 had detectable ctDNA post-NAC. Pts with recurrence/non-responders had a significantly higher mutation count 3 months after RC compared to responders, with a median of 7 vs. 0 mutations, respectively. Two pts with CR had detectable ctDNA at 3 months post-RC but have not recurred (Table). Conclusions: Clearance of ctDNA post-NAC correlated with pathologic complete response. Approximately 70% of pts had ctDNA clearance on NAC. All pts with residual disease at RC had detectable ctDNA post-NAC. [Table: see text]
Natural history of patients with muscle metastases from renal cell carcinoma: Results of the French national ARTEMIS study.
Authors: Mylene Wespiser, Lucia Carril-Ajuria, Blazevic Ilfad, Constance Thibault, Aude Flechon, Sophie Martin, Mathieu Laramas, Delphine Borchiellini, Camille Simon, Hakim Mahammedi, Claude Linassier, Morgan Goujon, Sonia Zaibet, Frederic Rolland, Laurence Albiges, Aurelia Meurisse, Antoine Falcoz, Antoine Thiery-Vuillemin
Journal: Journal of Clinical Oncology (2023)

618 Background: Muscle metastases (MM) are among rare secondary locations in renal cell carcinoma (RCC). Current guidelines do not provide specific advice on the management of these patients. There is a lack of scientific literature on the subject, mainly based on case reports or small retrospective monocentric cohorts. To date, therefore, there remains uncertainty about the clinical history, prognosis, and appropriate management of patients with MM. Methods: ARTEMIS is an ambispective national French multicenter, non-interventional study. It was opened to patients with metastatic RCC who had MM. The study was designed to assess overall survival (OS), progression-free survival (PFS), describe diagnostic and treatment modalities, and treatment-related serious adverse events in case of local treatments (TR-SAEs). Results: Median follow-up was 74.4 months IC95% [38.7-84.1]. The 146 enrolled patients were 73.6% male, with a median age of 57.6 years at diagnosis. They were initially diagnosed with stage IV RCC for 40.4% of them and had a favorable (36.2%), intermediate (45.7%), or poor (18.1%) IMDC risk score at the onset of metastases. Initially, metastases were mainly located in the lungs (55.5%), lymph nodes (26.7%), and bones (24.0%). Patients had a history of partial or total nephrectomy in 78.8% of cases. There were 30.0% of patients with synchronous MM. The median times from initial diagnosis or metastatic status to MM discovery were 25.5 [16.8-35.7] months and 8.4 [5.0-13.5] months, respectively. The majority (69.0%) of MM were discovered on conventional injected CT scans, whereas 8.3% were diagnosed clinically. Survival data are displayed on the table. Thirty-seven (25.3%) patients received local treatment of their MM which consisted of: external radiotherapy (48.6%), surgery (27.0%), cryotherapy (27.0%), stereotactic radiotherapy (5.4%), embolization (2.7%). Among them, local treatments prevented local relapse of MM in 28 patients (75.7%). Local TR-SAEs were seen in two patients (5.4%). Conclusions: ARTEMIS is the largest published cohort describing the disease history of patients with RCC suffering from MM. To our knowledge, this is the first study reporting the diagnostic and treatment modalities, also survival data. Despite its low incidence, the issue of these patients is not so rare in physicians’ practice. This work thus allows a greater understanding of clinical features and treatment of this pathology. [Table: see text]
The survival outcomes of metastatic non-clear cell renal cell carcinoma in the immunotherapy era: Princess Margaret Cancer Centre (PMCC) experience.
Authors: Esmail Mutahar Al-Ezzi, Abhenil Mittal, Zachary William Neil Veitch, Amer Zahralliyali, Nely Mercy Diaz Mejia, Osama Abdeljalil, Husam Alqaisi, Vikaash Kumar, Nazanin Fallah-Rad, Srikala S. Sridhar
Journal: Journal of Clinical Oncology (2023)

636 Background: Immunotherapy (IO) with or without targeted therapy (TT) is the standard treatment for patients (pts) with advanced clear cell renal cell carcinoma. The evidence to support their use in metastatic non-clear cell renal cell carcinoma (nccRCC) is based on smaller prospective trials and retrospective analyses. Here, we report the survival outcomes of pts with nccRCC treated with IO containing regimens or TT. Methods: This retrospective survival analysis was performed in metastatic nccRCC pts treated with IO and/or TT at the PMCC, Toronto between 2002 and 2021. Demographics, disease characteristics and survival outcomes were collected. Overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meier method (log-rank). Chi-square and fisher’s exact tests were used to evaluate response rates where appropriate. Interaction between variables was estimated using Cox proportional hazards. Results: We identified 530 metastatic RCC pts, of these 69 (13%) were nccRCC treated either with an IO containing regimen or TT. Among nccRCC pts, 42 (60.9%) had papillary subtype, 10 (14.5%) chromophobe, 14 (20.3%) unclassified, and 3 (4.3%) had an XP translocation. Median age was 54 years (range: 26-75) and 48 (69.5%) were male. Overall, as per the IMDC score, 15 (21.7%), 41 (59.5%) and 13 (18.8%) pts were categorized as good, intermediate and poor risk, respectively. Median follow-up was 116 months (95%CI: 30.8-201.1 months). Pts received sunitinib (n=41), ipilimumab plus nivolumab (n=8), sorafenib (n=5), savolitinib (n=3), pembrolizumab (n=3), pazopanib (n=2), temsirolimus (n=2), pembrolizumab plus axitinib (n=1), and other TT (n=4) in the first line treatment. Everolimus (n=13), nivolumab (n=7), sunitinib (n=7), axitinib (n=2), cabozantinib (n=2), chemotherapy (n=2), pembrolizumab plus axitinib (n=1), and other TT (n=2) were given in the second line treatment. The survival outcomes and responses are shown in the table. There was no interaction between age, gender, IMDC, RCC subtypes and survival outcomes. Conclusions: While the number of pts included in our retrospective review was small, our analysis suggested that pts with metastatic nccRCC have improved survival outcomes with IO containing regimens. Validation in a prospective dataset is required before widespread clinical utilization and many trials are currently ongoing. [Table: see text]